Role of 20-HETE in the antihypertensive effect of transfer of chromosome 5 from Brown Norway to Dahl salt-sensitive rats

Jan M. Williams, Fan Fan, Sydney Murphy, Carlos Schreck, Jozef Lazar, Howard J. Jacob, Richard J. Roman

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

This study examined whether substitution of chromosome 5 containing the CYP4A genes from Brown Norway rat onto the Dahl S salt-sensitive (SS) genetic background upregulates the renal production of 20-HETE and attenuates the development of hypertension. The expression of CYP4A protein and the production of 20-HETE were significantly higher in the renal cortex and outer medulla of SS.5 BN (chromosome 5-substituted Brown Norway rat) consomic rats fed either a low-salt (LS) or high-salt (HS) diet than that seen in SS rats. The increase in the renal production of 20-HETE in SS.5 BN rats was associated with elevated expression of CYP4A2 mRNA. MAP measured by telemetry rose from 117 ± 1 to 183 ± 5 mmHg in SS rats fed a HS diet for 21 days, but only increased to 151 ± 5 mmHg in SS.5 BN rats. The pressure-natriuretic and diuretic responses were twofold higher in SS.5 BN rats compared with SS rats. Protein excretion rose to 354 ± 17 mg/day in SS rats fed a HS diet for 21 days compared with 205 ± 13 mg/day in the SS.5 BN rats, and the degree of glomerular injury was reduced. Baseline glomerular capillary pressure (Pgc) was similar in SS.5 BN rats (43 ± 1 mmHg) and Dahl S (44 ± 2 mmHg) rats. However, Pgc increased to 59 ± 3 mmHg in SS rats fed a HS diet for 7 days, while it remained unaltered in SS.5 BN rats (43 ± 2 mmHg). Chronic administration of an inhibitor of the synthesis of 20-HETE (HET0016, 10 mg·kg -1·day -1 iv) reversed the antihypertensive phenotype seen in the SS.5 BN rats. These findings indicate that the transfer of chromosome 5 from the BN rat onto the SS genetic background increases the renal expression of CYP4A protein and the production of 20-HETE and that 20-HETE contributes to the antihypertensive and renoprotective effects seen in the SS.5 BN consomic strain.

Original languageEnglish (US)
Pages (from-to)R1209-R1218
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume302
Issue number10
DOIs
StatePublished - May 15 2012
Externally publishedYes

Keywords

  • Chromosome 5
  • Dahl S rats
  • Glomerulosclerosis
  • Hypertension
  • Kidney
  • Pressure natriuresis
  • Renal hemodynamics

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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